scholarly journals Pocket 4 of the HLA-DR(α,β 1*0401) molecule is a major determinant of T cells recognition of peptide.

1995 ◽  
Vol 181 (3) ◽  
pp. 915-926 ◽  
Author(s):  
X T Fu ◽  
C P Bono ◽  
S L Woulfe ◽  
C Swearingen ◽  
N L Summers ◽  
...  

To investigate the functional roles of individual HLA-DR residues in T cell recognition, transfectants expressing wild-type or mutant DR(alpha,beta 1*0401) molecules with single amino acid substitutions at 14 polymorphic positions of the DR beta 1*0401 chain or 19 positions of the DR alpha chain were used as antigen-presenting cells for five T cell clones specific for the influenza hemagglutinin peptide, HA307-19. Of the six polymorphic positions in the DR beta floor that were examined, mutations at only two positions eliminated T cell recognition: positions 13 (four clones) and 28 (one clone). In contrast, individual mutations at DR beta positions 70, 71, 78, and 86 on the alpha helix eliminated recognition by each of the clones, and mutations at positions 74 and 67 eliminated recognition by four and two clones, respectively. Most of the DR alpha mutations had minimal or no effect on most of the clones, although one clone was very sensitive to changes in the DR alpha chain, with loss of recognition in response to 10 mutants. Mutants that abrogated recognition by all of the clones were assessed for peptide binding, and only the beta 86 mutation drastically decreased peptide binding. Single amino acid substitutions at polymorphic positions in the central part of the DR beta alpha helix disrupted T cell recognition much more frequently than substitutions in the floor, suggesting that DR beta residues on the alpha helix make relatively greater contributions than those in the floor to the ability of the DR(alpha,beta 1*0401) molecule to present HA307-19. The data indicate that DR beta residues 13, 70, 71, 74, and 78, which are located in pocket 4 of the peptide binding site in the crystal structure of the DR1 molecule, exert a major and disproportionate influence on the outcome of T cell recognition, compared with other polymorphic residues.

Science ◽  
1986 ◽  
Vol 231 (4735) ◽  
pp. 255-258 ◽  
Author(s):  
M. Brown ◽  
L. Glimcher ◽  
E. Nielsen ◽  
W. Paul ◽  
R. Germain

1990 ◽  
Vol 172 (1) ◽  
pp. 273-283 ◽  
Author(s):  
R W Karr ◽  
W Yu ◽  
R Watts ◽  
K S Evans ◽  
E Celis

The relative importance of 11 polymorphic positions in the HLA-DR7 beta 1 chain in T cell recognition of foreign antigens was investigated using transfectants expressing mutant DR7 beta 1 chains as APC for five rabies virus-specific T cell clones. The results indicate that multiple amino acids, located in both the beta-strands and alpha-helix of DR7 beta 1 in the model of a class II molecule, are involved in DR7-restricted T cell recognition of these antigens. Many of the substitutions appeared to reduce the affinity of an antigenic peptide for the mutant DR7 molecules but did not prevent binding. The heterogeneity of responses of the three G-specific T cell clones to presentation of the G11.3 peptide by several of the mutant DR7 molecules indicates that the T cell receptor (TCR) of each these clones requires a different view of the G11.3/DR7 complex and raises the possibility that the G11.3 peptide may bind to the DR7 molecule in more than one conformation.


1995 ◽  
Vol 42 (2) ◽  
pp. 145-153 ◽  
Author(s):  
Gunnar Paulsen ◽  
Knut E.A. Lundin ◽  
Henrik A. Gjertsen ◽  
Torbjørn Hansen ◽  
Ludvig M. Sollid ◽  
...  

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1811-1811
Author(s):  
Eleanor M. Lanning ◽  
Peter G. Middleton ◽  
Anne M. Dickinson ◽  
Ernst Holler ◽  
Eliane Gluckman ◽  
...  

Abstract On behalf of Eurobank Members CD1a is a lipid antigen-presenting protein related to MHC class I that is frequently but incorrectly said to be non-polymorphic. There are two alleles in humans that differ by two linked amino acid substitutions, I13T and W51C in the alpha-1 domain. Substitution of threonine and cysteine in the minor allele may modify the structure of the antigen-binding groove and influence antigen specificity and T cell recognition. The CD1a gene on chromosome 1 may be mismatched in MHC identical sibling transplants, but the effect of this on GVHD is unknown. We hypothesized that CD1a might act as a tissue antigen and that GVHD would increase in recipients who possessed an allele unknown to the donor. 163 recipient-donor sibling pairs transplanted with full and reduced intensity conditioning but without T depletion were identified from a database of all sequential transplants performed in Newcastle from Nov 1984 to Sept 2004 and in collaborating Eurobank centres from Nov 1997 to Sept 2004. DNA was amplified by PCR primers 5′: CCTGGAAACAAAATCTGGTC and 3′: GGGTACTTAACGTCAAACTT producing a 209 bp fragment, encompassing the C to G substitution at nucleotide 738 (W51C). This was analysed by SSCP and RFLP using the Hae III site 737–741. The overall allele frequency was: allele 1 (I13; W51): 0.07; allele 2 (T13; C51): 0.93. 148 pairs were matched at CD1a (2,2 into 2,2 or 1,2 into 1,2) and 15 were unmatched in the GVHD direction (2,2 into 1,2). There were no significant differences between the cohorts in age, gender mismatch, conditioning or transplant center. 5 year projected survival was 57% months in the matched cohort and 59% months in the unmatched (p=0.10 Kaplan-Meier). 43/148 (29%) matched transplants received cyclosporin alone GVHD prophylaxis compared with 9/15 (60%) of unmatched transplants (p=0.01; Fisher’s exact test). The incidence and severity of GVHD was similar in both matched and unmatched cohorts: grade I–IV: 81% and 87% respectively (p=0.59); II–IV: 61% and 62% (p=0.48); III–IV: 22% and 20% (p=0.51; Fisher’s exact test). The use of less GVHD prophylaxis in the unmatched group strengthens a negative result and as predicted, no increase in risk due to mismatching was revealed after correction for GVHD prophylaxis and other variables by binomial logistic regression. CD1a is an antigen-presenting molecule important in host defense. It is dimorphic in humans with a minor allele found in 16% of individuals and mismatched in the GVHD direction in 9% of HLA-identical sibling allogeneic transplants. Although amino acid substitution may alter the antigen specificity of the two isoforms of CD1a, mismatching does not increase the risk of GVHD and therefore CD1a does not appear to function as a tissue antigen in transplantation. This functional result supports recent structural analysis of the CD1a-TCR interaction showing that the glycolipid antigen makes little contribution to TCR binding, in contrast to the peptide antigens of conventional class I MHC molecules, which play an essential role in T cell recognition (Zajonc et al. Immunity2005. 22: 209–19).


1998 ◽  
Vol 59 (3) ◽  
pp. 149-157 ◽  
Author(s):  
Dawei Ou ◽  
Leslie Ann Mitchell ◽  
Diane Décarie ◽  
Aubrey J Tingle ◽  
Gerald T Nepom

2007 ◽  
Vol 68 (1) ◽  
pp. S13
Author(s):  
Christina Bade-Doeding ◽  
Axel Seltsam ◽  
Holger-Andreas Elsner ◽  
Britta Eiz-Vesper ◽  
Constanca Figueiredo ◽  
...  

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